ATP-sensitive potassium channels (KATP) are heteromeric channels consisting of two subunits: (I) an ATPbinding cassette protein, the SuIfonylUREA receptor (SUR; e.g. SUR1, SUR2), and (ii) an Inwardly rectifying potassium (j about) channel subunit (Kir6; e.g. Kir6.1, Kir6.2). Distinct combinations of these two subunits give rise to different native KATP channels. KATP channels, in the pancreas for example, are formed from SUR1 and Kir6.2. KATP channels serve as important links coupling the metabolic state of a cell to membrane excitability. In the pancreas, mutations in each of the two subunits are correlated with the recessive disorder Persistent Hyperinsulinemic Hypoglycemia of infancy (PHHI). Patients with PHHI possess defective pancreatic KATP channels, resulting in unregulated insulin secretion. It is now accepted that the K1r6 subunit forms the channel pore, while the SUR subunit confers to the channel its novel pharmacological characteristics, such as inhibition by sulfonylureas (SU), and activation by potassium channel openers (KCO). SUR/Kir6 heteromeric channels also show higher sensitivity to ATP inhibition and higher channel density on the cell surface compared to the homomeric K1r6 channels. Hence, a molecular understanding of how the SUR and K1r6 subunits interact with each other is of crucial importance to the understanding of KATP channel function. All ABC proteins are made up of two transmembrane domains (TMDI and TMDII), each consisting of six membrane segments. In addition, each TMD domain is followed by a cytoplasmic nucleotide binding domain (NBD1 and NBD2). SUR is closely related to a subfamily within the ABC family of proteins that includes the multidrug resistance-associated proteins (MRP) and the yeast cadmium transporter. Members of this subfamily contain an extra N-terminal transmembrane domain (TMDO), which is made up of five membrane segments. Specific mutations that are correlated with the PHHI phenotype are found in the TMDO of SUR1. Here, we present evidences that the TMDO of SUR1 affects the surface expression and the gating of the Kir6.2 subunit by physically associating with it. These results underscore the importance of the TMDO of SUR as an important structural element involved in the interactions with K1r6. My application aims to elucidate the role of the TMDO in the function of the KATP channel.